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Clozapine-induced severe mixed hyperlipidemia: a case report
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General Hospital Psychiatry 31 (2009) 93 – 96
Clozapine-induced severe mixed hyperlipidemia: a case report Mohamed Ahmed, M.B.B.S., M.Med.Sci., M.R.C.Psych.a,⁎, Damian Griffin, M.B., B.Ch., B.A.O., M.Sc., M.R.C.Path., M.D.b , Ray O'Toole, M.R.C.Psych., F.R.C.P.(C)c , Colm McDonald, M.B., M.R.C.Psych., Ph.D.a a
Department of Psychiatry, National University of Ireland Galway, Galway, Ireland b Department of Clinical Biochemistry, University Hospital, Galway, Ireland c Department of Psychiatry, University Hospital, Galway, Ireland Received 19 May 2008; accepted 8 July 2008
Abstract Objective: To highlight the association between the use of clozapine and the early development of severe mixed hyperlipidemia, a condition that substantially increases the risk of cardiovascular events and other medical complications. Method: Clinical information and data from investigations in a single patient were collated and reviewed in light of the literature. Results: A 47-year-old man with a background history of schizophrenia taking clozapine presented with multiple episodes of severe elevation of serum triglycerides and cholesterol with subsequent development of diabetes mellitus. His metabolic parameters normalized following discontinuation of clozapine. Conclusion: Lipid and metabolic profiles should be closely monitored in patients receiving clozapine in order to facilitate early detection and intervention to prevent further health complications. © 2009 Elsevier Inc. All rights reserved. Keywords: Clozapine; Severe mixed hyperlipidemia; Hypertriglyceridemia
1. Introduction In recent years, treatment with antipsychotic medication has been recognized as a risk factor for the development of lipid and glucose dysregulation. Accumulating evidence indicates that atypical antipsychotic medications have a greater propensity to produce lipid abnormalities, especially those medications most strongly associated with weight gain such as clozapine and olanzapine [1]. Clozapine remains the only antipsychotic medication with established efficacy in treatment-resistant schizophrenia patients [2]. Despite its efficacy, clozapine has a significant impact on metabolic parameters. Clozapine is associated with substantial weight gain [3], hypertriglyceridemia [4], hypercholesterolemia [5], and hypertension [6].
⁎ Corresponding author. Tel.: +353 877787405. E-mail address: [email protected] (M. Ahmed). 0163-8343/$ – see front matter © 2009 Elsevier Inc. All rights reserved. doi:10.1016/j.genhosppsych.2008.07.003
We describe a case demonstrating the association between clozapine treatment and severe mixed hyperlipidemia precipitating an episode of acute pancreatitis. 2. Case report Mr. J.C., a 47-year-old Caucasian man, was diagnosed with schizophrenia at 23 years of age when he presented with auditory hallucinations in the third person, persecutory delusions, thought insertion and thought broadcasting. From 23 to 33 years of age, he required 12 admissions to the local psychiatric inpatient unit, during which he took various antipsychotic medications including thioridazine, chlorpromazine, sulpiride and haloperidol. His response was poor with persistent delusions and hallucinations. He was unable to work or to live independently. He was considered treatment resistant and commenced on clozapine at 33 years of age and was maintained on 450 mg daily with an average clozapine plasma level of 490 ng/mL. All other psychotropic medications were discontinued.
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M. Ahmed et al. / General Hospital Psychiatry 31 (2009) 93–96
Mr. JC improved substantially on clozapine with gradual remission of his psychotic symptoms. Two months after commencing clozapine, he was able to work and to live independently. He required no psychiatric admissions in the subsequent 14 years. Prior to commencing clozapine, Mr. JC had no history of significant physical illnesses and in particular no history of abnormal lipids or elevated blood glucose. Baseline (i.e., preclozapine commencement) cholesterol was 157.5 mg/dl (normal b195 mg/dl), triglycerides 150.3 mg/dl (normal b178 mg/dl) and glucose 94.2 mg/dl (normal b100.8 mg/dl). He was not known to have any family history of hyperlipidemia, ischemic heart disease or diabetes mellitus. At 35 years of age, 2 years after commencing clozapine, Mr. JC saw a dermatologist because of new-onset skin lesions that were diagnosed as xanthomas. Such lesions usually develop with very high cholesterol and triglycerides. At that time, his fasting cholesterol level was 772.2 mg/dl (normal b195 mg/dl), fasting triglycerides level was 4886.1 mg/dl (normal b178 mg/dl) and fasting glucose level was 94.6 mg/ dl (normal b100.8 mg/dl). He was then commenced on atorvastatin 10 mg daily with a dietary regimen of low fat. Meanwhile, he continued to take 450 mg clozapine daily with an excellent level of functioning. Follow-up blood investigations showed some response to statin treatment; nevertheless, fasting lipids were always above the normal range with an average of 223 mg/dl for fasting cholesterol (normal b195 mg/dl) and 300 mg/dl for fasting triglycerides (normal b178 mg/dl) over the 11 years of statin treatment. His glycemic status remained normal during this period. Mr. JC gained some body weight with clozapine treatment, and his body mass index (BMI) rose from 23.9 at baseline (i.e., pre clozapine commencement) to 26.2 six months after commencing clozapine. His BMI ranged between 25.9 and 27.5 during 14 years of clozapine treatment, and the maximum weight gain recorded was 11.5 kg. At the age of 46, Mr. JC was admitted surgically with acute abdominal pain radiating to his back. He had an elevated amylase level of 198 U/L (normal b100 U/L), and the working diagnosis was acute pancreatitis. Following admission, Mr. JC was noted to have extreme elevation of cholesterol levels at 1404 mg/dl (normal b195 mg/dl) and triglyceride levels at 14,418 mg/dl (normal b178 mg/dl). His fasting glucose level was 147.6 mg/dl (normal b100.8 mg/dl). This was his first time to be diagnosed with diabetes mellitus. During this admission, lipid- and glucose-lowering drugs were administered (fenofibrate 200 mg daily, ω-3-acid ethyl esters 1 g daily and metformin 500 mg three times daily) and clozapine treatment was withheld. Within 3 weeks his metabolic parameters had normalized with fasting cholesterol of 187.7 mg/dl (normal b195 mg/dl), triglycerides of 165.8 mg/dl (normal b178 mg/dl) and fasting glucose of 96.6 mg/dl (normal b100.8 mg/dl). At that stage, Mr. JC was medically stable but his psychotic symptoms greatly deteriorated. Clozapine was
recommenced and titrated up to 400 mg daily; however, within 10 weeks, cholesterol had increased to 417.3 mg/dl (normal b195 mg/dl), triglyceride to 3008.2 mg/dl (normal b178 mg/dl) and fasting glucose to 167.4 mg/dl (normal b100.8 mg/dl) despite continued administration of lipid- and glucose-lowering drugs. Consequently, clozapine was discontinued, and 10 days later, metabolic parameters again normalized with fasting cholesterol of 167.7 mg/dl (normal b195 mg/dl), fasting triglycerides of 195.8 mg/dl (normal b178 mg/dl) and fasting glucose of 95.8 mg/dl (normal b100.8 mg/dl). His metabolic parameters continued within the normal range for 3 months following clozapine discontinuation, during which he was taking aripiprazole 30 mg daily in addition to his usual lipid- and glucose-lowering drugs. However, his mental state deteriorated with emergence of delusions and hallucinations associated with a marked decline in his social and occupational functioning. Subsequently, Mr. JC was switched to olanzapine 20 mg daily, which partially helped his symptom control but was also associated with some elevation in his fasting metabolic parameters as cholesterol increased to 222.3 mg/dl (normal b195 mg/dl), triglycerides to 590.1 mg/dl (normal b178 mg/ dl) and glucose to 128.3 mg/dl (normal b100.8 mg/dl) despite adherence to his usual lipid- and glucose-lowering drugs. He required two psychiatric admissions within 3 months and, at present, he is unable to work or live independently. Genetic testing revealed that Mr. JC did not have the E2/ E2 apolipoprotein E phenotype commonly associated with type III hyperlipoproteinemia, making the probability of this as an explanation for his dyslipidemia highly unlikely.
3. Discussion This patient developed severe mixed hyperlipidemia apparently as a result of exposure to clozapine within moderate dosage ranges. His serum level of triglycerides during his recent surgical admission was over 80 times the normal maximum limit. Although accuracy of laboratory equipment deteriorates at such high levels, this was clearly an extraordinarily high level, and reported measurements of severe hypertriglyceridemia in the literature are far below this. His lipid profile normalized following discontinuation of clozapine and commencement of lipid-lowering medication but immediately rose again on reintroducing clozapine. Although Mr. JC gained some weight with clozapine treatment, this was not extensive and he remained within the overweight rather than the obese range. There is an emerging literature which indicates that atypical antipsychotic medications have direct and immediate effects on serum lipid levels that go beyond obesity effects [7]. The CATIE Schizophrenia Trial has confirmed the differences in metabolic impact among atypical antipsychotic medications even during brief periods of exposure [8]. Clozapine, olanzapine and quetiapine in particular appear to display a high propensity to
M. Ahmed et al. / General Hospital Psychiatry 31 (2009) 93–96
induce glucose dysregulation and dyslipidemia possibly due to insulin resistance, increased appetite and related endocrine changes in predisposed individuals [8,9]. The risk for diabetes appears to follow roughly the risk for weight gain, being highest for clozapine and olanzapine, intermediate with quetiapine and risperidone and lowest for aripiprazole and ziprasidone [10]. It was considered that Mr. JC might have type III hyperlipoproteinemia (a.k.a. broad beta disease, dysbetalipoproteinemia and remnant removal disease). In type III hyperlipoproteinemia, patients develop a marked mixed hyperlipidemia, often with striate palmar xanthomas or tuberose xanthomas. It can be precipitated by obesity, diabetes or hypothyroidism in genetically predisposed individuals. Most cases (N90%) are associated with homozygosity for a variant of the apolipoprotein E gene (E2/E2) that occurs in 0.2–1.6% of unselected populations[11]. This results in defective clearance of chylomicron remnants and intermediate-density lipoprotein remnants. Isoelectric focusing showed Mr. JC did not have the E2/E2 phenotype. The mechanisms responsible for developing lipid and carbohydrate abnormalities in patients taking atypical antipsychotics are not clearly understood. However, the diverse receptor binding nature of atypical antipsychotics may be associated with their potential to elevate glucose and lipid levels. Antagonism at 5-HT2C receptors may be associated with the weight gain induced by clozapine and olanzapine as 5-HT2C receptors are probably involved in the regulation of food intake [12]. Antimuscarinic effects of clozapine might interfere with glucose utilization, and in the liver, release of acetylcholine from parasympathetic nerve endings has been shown to increase hepatic glucose uptake in preclinical models [12]. Individual genetic variations are likely to confer different sensitivity to antipsychotics in relation to hyperlipidemia [12]. De Leon et al. [13] recently reported that genotypic variation of certain single nucleotide polymorphisms (SNPs) in three biologically plausible genes were associated with hypertriglyceridemia or hypercholesterolemia in patients taking three antipsychotic medications — olanzapine, quetiapine and chlorpromazine. These included a genotypic variation in the acetylcoenzyme A carboxylase α (ACCα) gene, a rate-limiting enzyme in the synthesis of long-chain fatty acids, and hypertriglyceridemia; and between hypercholesterolemia and single-nucleotide polymorphisms (SNPs) in the neuropeptide Y (NPY) and acetyl-coenzyme A carboxylase β (ACCβ) genes. NPY is a potent stimulator of food intake and influences lipid metabolism. ACCβ appears to be involved in mitochondrial fatty acid oxidation and produces malonyl-CoA, which may act centrally to control food intake through production of hypothalamic NPY [12]. Given these preliminary findings, pharmacogenetic testing may prove useful in predicting the potential for dysregulation of intermediary metabolism in individual patients being started on antipsychotic medication.
95
Clozapine remains the most effective agent for the treatment of refractory schizophrenia, producing response in 30% of patients with treatment-resistant schizophrenia in the seminal 6-week trial by Kane et al. [2] and up to 60% response at 6 months [14]. It is likely that the benefits of switching this medication to one less likely to result in dysregulation of intermediary metabolism will be outweighed by its clinical benefit for most patients. There is increasing research to indicate that fasting lipids should be evaluated annually rather than every 5 years as was initially recommended by the guidelines of the American Diabetes Association–American Psychiatric Association (2004) given the high rate of untreated dyslipidemia among patients prescribed atypical antipsychotics [15–18]. Effective metabolic monitoring of this patient population requires educating physicians, dissemination of educational material among patients and developing systems for recording, and interpreting data as well as defining responsibility for these tasks [15]. Other clinical measures include improvement in lifestyle-related behaviors (diet, exercise, smoking habits) and complying with pharmacological management of glucose and lipid dysregulation where indicated. This unusual case report highlights the metabolic complications of the most efficacious antipsychotic medication and underlines the need to physically monitor this patient population. References [1] De Hert M, Van Eyeck D, De Nayer A. Metabolic abnormalities associated with second generation antipsychotics: fact or fiction? Development of guidelines for screening and monitoring. Int Clin Psychopharmacol 2006;21:1–5. [2] Kane J, Honigfeld G, Singer J, Meltzer H. Clozapine for the treatmentresistant schizophrenic: a double-blind comparison with chlorpromazine. Arch Gen Psychiatry 1998;45:789–96. [3] Allison DB, Mentore JM, Heo M, et al. Antipsychotic-induced weight gain: a comprehensive research synthesis. Am J Psychiatry 1999;156: 1686–96. [4] Meyer JM, Koro CE. The effects of antipsychotic therapy on serum lipids: a comprehensive review. Schizophr Res 2004;70:1–17. [5] Casey DE. Dyslipidemia and atypical antipsychoic drugs. J Clin Psychiatry 2004;65:27–35. [6] Henderson DC, Daley TB, Kunkel L, et al. Clozapine and hypertension: a chart review of 82 patients. J Clin Psychiatry 2004; 65:686–9. [7] de Leon J, Susce MT, Johnson M, et al. A clinical study of the association of antipsychotics with hyperlipidemia. Schizophr Res 2007;92:95–102. [8] Meyer JM, Davis VG, Goff DC, McEvoy JP, Nasrallah HA, Davis SM, Rosenheck RA, Daumit GL, Hsiao J, Swartz MS, Stroup TS, Lieberman JA. Change in metabolic syndrome parameters with antipsychotic treatment in the CATIE Schizophrenia Trial: prospective data from phase 1. Schizophr Res 2008;101:273–86. [9] Baptista T, Kin NMKNY. Obesity and related metabolic abnormalities during antipsychotic drug administration: mechanisms, management and research perspectives. Pharmacopsychiatry 2002;35: 205–19. [10] Correll C. Balancing efficacy and safety in treatment with antipsychotics: an expert review of clinical challenges in psychiatry. CNS Spectr. 2007;12:10 (Suppl 17):12–20, 35.
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[11] Utermann G. Apolipoprotein E polymorphisms in health and disease. Am Heart J 1987;113:433–40. [12] Arulmozhi DK, Dwyer DS, Bodhankar SL. Antipsychotic induced metabolic abnormalities: an interaction study with various PPAR modulators in miceLife. Sciences 2006;79(19):1865–72. [13] de Leon J, Correa JC, Ruaño G, et al. Exploring genetic variations that may be associated with the direct effects of some antipsychotics on lipid levels. Schizophr Res 2008;98(1-3):40–6. [14] Meltzer HY, Burnett S, Bastani B, Ramirez LF. Effect of six months of clozapine treatment on the quality of life of chronic schizophrenic patients. Hosp Community Psychiatry 1990;41:892–7. [15] Cohn TA, Sernyak MJ. Metabolic monitoring for patients treated with antipsychotic medications. Can J Psychiatry 2006;51:492–501.
[16] De Hert M, van Eyck D, De Nayer A. Metabolic abnormalities associated with second generation antipsychotics: fact or fiction? Development of guidelines for screening and monitoring. Int Clin Psychopharmacol 2006;21:S11–6. [17] American Diabetes Association, American Psychiatric Association, American Association of Clinical Endocrinologists, North American Association for the Study of Obesity. Consensus development conference on antipsychotic drugs and obesity and diabetes. Diabetes Care 2004;27:596–601. [18] Nasrallah H, McEvoy J, Meyer J, Goff D, Davis S. Low rates of treatment for metabolic disorders in the CATIE schizophrenia trial at baseline: healthcare disparities in schizophrenia. Neuropsychopharmacology 2005;30:S204.
General Hospital Psychiatry 31 (2009) 93 – 96
Clozapine-induced severe mixed hyperlipidemia: a case report Mohamed Ahmed, M.B.B.S., M.Med.Sci., M.R.C.Psych.a,⁎, Damian Griffin, M.B., B.Ch., B.A.O., M.Sc., M.R.C.Path., M.D.b , Ray O'Toole, M.R.C.Psych., F.R.C.P.(C)c , Colm McDonald, M.B., M.R.C.Psych., Ph.D.a a
Department of Psychiatry, National University of Ireland Galway, Galway, Ireland b Department of Clinical Biochemistry, University Hospital, Galway, Ireland c Department of Psychiatry, University Hospital, Galway, Ireland Received 19 May 2008; accepted 8 July 2008
Abstract Objective: To highlight the association between the use of clozapine and the early development of severe mixed hyperlipidemia, a condition that substantially increases the risk of cardiovascular events and other medical complications. Method: Clinical information and data from investigations in a single patient were collated and reviewed in light of the literature. Results: A 47-year-old man with a background history of schizophrenia taking clozapine presented with multiple episodes of severe elevation of serum triglycerides and cholesterol with subsequent development of diabetes mellitus. His metabolic parameters normalized following discontinuation of clozapine. Conclusion: Lipid and metabolic profiles should be closely monitored in patients receiving clozapine in order to facilitate early detection and intervention to prevent further health complications. © 2009 Elsevier Inc. All rights reserved. Keywords: Clozapine; Severe mixed hyperlipidemia; Hypertriglyceridemia
1. Introduction In recent years, treatment with antipsychotic medication has been recognized as a risk factor for the development of lipid and glucose dysregulation. Accumulating evidence indicates that atypical antipsychotic medications have a greater propensity to produce lipid abnormalities, especially those medications most strongly associated with weight gain such as clozapine and olanzapine [1]. Clozapine remains the only antipsychotic medication with established efficacy in treatment-resistant schizophrenia patients [2]. Despite its efficacy, clozapine has a significant impact on metabolic parameters. Clozapine is associated with substantial weight gain [3], hypertriglyceridemia [4], hypercholesterolemia [5], and hypertension [6].
⁎ Corresponding author. Tel.: +353 877787405. E-mail address: [email protected] (M. Ahmed). 0163-8343/$ – see front matter © 2009 Elsevier Inc. All rights reserved. doi:10.1016/j.genhosppsych.2008.07.003
We describe a case demonstrating the association between clozapine treatment and severe mixed hyperlipidemia precipitating an episode of acute pancreatitis. 2. Case report Mr. J.C., a 47-year-old Caucasian man, was diagnosed with schizophrenia at 23 years of age when he presented with auditory hallucinations in the third person, persecutory delusions, thought insertion and thought broadcasting. From 23 to 33 years of age, he required 12 admissions to the local psychiatric inpatient unit, during which he took various antipsychotic medications including thioridazine, chlorpromazine, sulpiride and haloperidol. His response was poor with persistent delusions and hallucinations. He was unable to work or to live independently. He was considered treatment resistant and commenced on clozapine at 33 years of age and was maintained on 450 mg daily with an average clozapine plasma level of 490 ng/mL. All other psychotropic medications were discontinued.
94
M. Ahmed et al. / General Hospital Psychiatry 31 (2009) 93–96
Mr. JC improved substantially on clozapine with gradual remission of his psychotic symptoms. Two months after commencing clozapine, he was able to work and to live independently. He required no psychiatric admissions in the subsequent 14 years. Prior to commencing clozapine, Mr. JC had no history of significant physical illnesses and in particular no history of abnormal lipids or elevated blood glucose. Baseline (i.e., preclozapine commencement) cholesterol was 157.5 mg/dl (normal b195 mg/dl), triglycerides 150.3 mg/dl (normal b178 mg/dl) and glucose 94.2 mg/dl (normal b100.8 mg/dl). He was not known to have any family history of hyperlipidemia, ischemic heart disease or diabetes mellitus. At 35 years of age, 2 years after commencing clozapine, Mr. JC saw a dermatologist because of new-onset skin lesions that were diagnosed as xanthomas. Such lesions usually develop with very high cholesterol and triglycerides. At that time, his fasting cholesterol level was 772.2 mg/dl (normal b195 mg/dl), fasting triglycerides level was 4886.1 mg/dl (normal b178 mg/dl) and fasting glucose level was 94.6 mg/ dl (normal b100.8 mg/dl). He was then commenced on atorvastatin 10 mg daily with a dietary regimen of low fat. Meanwhile, he continued to take 450 mg clozapine daily with an excellent level of functioning. Follow-up blood investigations showed some response to statin treatment; nevertheless, fasting lipids were always above the normal range with an average of 223 mg/dl for fasting cholesterol (normal b195 mg/dl) and 300 mg/dl for fasting triglycerides (normal b178 mg/dl) over the 11 years of statin treatment. His glycemic status remained normal during this period. Mr. JC gained some body weight with clozapine treatment, and his body mass index (BMI) rose from 23.9 at baseline (i.e., pre clozapine commencement) to 26.2 six months after commencing clozapine. His BMI ranged between 25.9 and 27.5 during 14 years of clozapine treatment, and the maximum weight gain recorded was 11.5 kg. At the age of 46, Mr. JC was admitted surgically with acute abdominal pain radiating to his back. He had an elevated amylase level of 198 U/L (normal b100 U/L), and the working diagnosis was acute pancreatitis. Following admission, Mr. JC was noted to have extreme elevation of cholesterol levels at 1404 mg/dl (normal b195 mg/dl) and triglyceride levels at 14,418 mg/dl (normal b178 mg/dl). His fasting glucose level was 147.6 mg/dl (normal b100.8 mg/dl). This was his first time to be diagnosed with diabetes mellitus. During this admission, lipid- and glucose-lowering drugs were administered (fenofibrate 200 mg daily, ω-3-acid ethyl esters 1 g daily and metformin 500 mg three times daily) and clozapine treatment was withheld. Within 3 weeks his metabolic parameters had normalized with fasting cholesterol of 187.7 mg/dl (normal b195 mg/dl), triglycerides of 165.8 mg/dl (normal b178 mg/dl) and fasting glucose of 96.6 mg/dl (normal b100.8 mg/dl). At that stage, Mr. JC was medically stable but his psychotic symptoms greatly deteriorated. Clozapine was
recommenced and titrated up to 400 mg daily; however, within 10 weeks, cholesterol had increased to 417.3 mg/dl (normal b195 mg/dl), triglyceride to 3008.2 mg/dl (normal b178 mg/dl) and fasting glucose to 167.4 mg/dl (normal b100.8 mg/dl) despite continued administration of lipid- and glucose-lowering drugs. Consequently, clozapine was discontinued, and 10 days later, metabolic parameters again normalized with fasting cholesterol of 167.7 mg/dl (normal b195 mg/dl), fasting triglycerides of 195.8 mg/dl (normal b178 mg/dl) and fasting glucose of 95.8 mg/dl (normal b100.8 mg/dl). His metabolic parameters continued within the normal range for 3 months following clozapine discontinuation, during which he was taking aripiprazole 30 mg daily in addition to his usual lipid- and glucose-lowering drugs. However, his mental state deteriorated with emergence of delusions and hallucinations associated with a marked decline in his social and occupational functioning. Subsequently, Mr. JC was switched to olanzapine 20 mg daily, which partially helped his symptom control but was also associated with some elevation in his fasting metabolic parameters as cholesterol increased to 222.3 mg/dl (normal b195 mg/dl), triglycerides to 590.1 mg/dl (normal b178 mg/ dl) and glucose to 128.3 mg/dl (normal b100.8 mg/dl) despite adherence to his usual lipid- and glucose-lowering drugs. He required two psychiatric admissions within 3 months and, at present, he is unable to work or live independently. Genetic testing revealed that Mr. JC did not have the E2/ E2 apolipoprotein E phenotype commonly associated with type III hyperlipoproteinemia, making the probability of this as an explanation for his dyslipidemia highly unlikely.
3. Discussion This patient developed severe mixed hyperlipidemia apparently as a result of exposure to clozapine within moderate dosage ranges. His serum level of triglycerides during his recent surgical admission was over 80 times the normal maximum limit. Although accuracy of laboratory equipment deteriorates at such high levels, this was clearly an extraordinarily high level, and reported measurements of severe hypertriglyceridemia in the literature are far below this. His lipid profile normalized following discontinuation of clozapine and commencement of lipid-lowering medication but immediately rose again on reintroducing clozapine. Although Mr. JC gained some weight with clozapine treatment, this was not extensive and he remained within the overweight rather than the obese range. There is an emerging literature which indicates that atypical antipsychotic medications have direct and immediate effects on serum lipid levels that go beyond obesity effects [7]. The CATIE Schizophrenia Trial has confirmed the differences in metabolic impact among atypical antipsychotic medications even during brief periods of exposure [8]. Clozapine, olanzapine and quetiapine in particular appear to display a high propensity to
M. Ahmed et al. / General Hospital Psychiatry 31 (2009) 93–96
induce glucose dysregulation and dyslipidemia possibly due to insulin resistance, increased appetite and related endocrine changes in predisposed individuals [8,9]. The risk for diabetes appears to follow roughly the risk for weight gain, being highest for clozapine and olanzapine, intermediate with quetiapine and risperidone and lowest for aripiprazole and ziprasidone [10]. It was considered that Mr. JC might have type III hyperlipoproteinemia (a.k.a. broad beta disease, dysbetalipoproteinemia and remnant removal disease). In type III hyperlipoproteinemia, patients develop a marked mixed hyperlipidemia, often with striate palmar xanthomas or tuberose xanthomas. It can be precipitated by obesity, diabetes or hypothyroidism in genetically predisposed individuals. Most cases (N90%) are associated with homozygosity for a variant of the apolipoprotein E gene (E2/E2) that occurs in 0.2–1.6% of unselected populations[11]. This results in defective clearance of chylomicron remnants and intermediate-density lipoprotein remnants. Isoelectric focusing showed Mr. JC did not have the E2/E2 phenotype. The mechanisms responsible for developing lipid and carbohydrate abnormalities in patients taking atypical antipsychotics are not clearly understood. However, the diverse receptor binding nature of atypical antipsychotics may be associated with their potential to elevate glucose and lipid levels. Antagonism at 5-HT2C receptors may be associated with the weight gain induced by clozapine and olanzapine as 5-HT2C receptors are probably involved in the regulation of food intake [12]. Antimuscarinic effects of clozapine might interfere with glucose utilization, and in the liver, release of acetylcholine from parasympathetic nerve endings has been shown to increase hepatic glucose uptake in preclinical models [12]. Individual genetic variations are likely to confer different sensitivity to antipsychotics in relation to hyperlipidemia [12]. De Leon et al. [13] recently reported that genotypic variation of certain single nucleotide polymorphisms (SNPs) in three biologically plausible genes were associated with hypertriglyceridemia or hypercholesterolemia in patients taking three antipsychotic medications — olanzapine, quetiapine and chlorpromazine. These included a genotypic variation in the acetylcoenzyme A carboxylase α (ACCα) gene, a rate-limiting enzyme in the synthesis of long-chain fatty acids, and hypertriglyceridemia; and between hypercholesterolemia and single-nucleotide polymorphisms (SNPs) in the neuropeptide Y (NPY) and acetyl-coenzyme A carboxylase β (ACCβ) genes. NPY is a potent stimulator of food intake and influences lipid metabolism. ACCβ appears to be involved in mitochondrial fatty acid oxidation and produces malonyl-CoA, which may act centrally to control food intake through production of hypothalamic NPY [12]. Given these preliminary findings, pharmacogenetic testing may prove useful in predicting the potential for dysregulation of intermediary metabolism in individual patients being started on antipsychotic medication.
95
Clozapine remains the most effective agent for the treatment of refractory schizophrenia, producing response in 30% of patients with treatment-resistant schizophrenia in the seminal 6-week trial by Kane et al. [2] and up to 60% response at 6 months [14]. It is likely that the benefits of switching this medication to one less likely to result in dysregulation of intermediary metabolism will be outweighed by its clinical benefit for most patients. There is increasing research to indicate that fasting lipids should be evaluated annually rather than every 5 years as was initially recommended by the guidelines of the American Diabetes Association–American Psychiatric Association (2004) given the high rate of untreated dyslipidemia among patients prescribed atypical antipsychotics [15–18]. Effective metabolic monitoring of this patient population requires educating physicians, dissemination of educational material among patients and developing systems for recording, and interpreting data as well as defining responsibility for these tasks [15]. Other clinical measures include improvement in lifestyle-related behaviors (diet, exercise, smoking habits) and complying with pharmacological management of glucose and lipid dysregulation where indicated. This unusual case report highlights the metabolic complications of the most efficacious antipsychotic medication and underlines the need to physically monitor this patient population. References [1] De Hert M, Van Eyeck D, De Nayer A. Metabolic abnormalities associated with second generation antipsychotics: fact or fiction? Development of guidelines for screening and monitoring. Int Clin Psychopharmacol 2006;21:1–5. [2] Kane J, Honigfeld G, Singer J, Meltzer H. Clozapine for the treatmentresistant schizophrenic: a double-blind comparison with chlorpromazine. Arch Gen Psychiatry 1998;45:789–96. [3] Allison DB, Mentore JM, Heo M, et al. Antipsychotic-induced weight gain: a comprehensive research synthesis. Am J Psychiatry 1999;156: 1686–96. [4] Meyer JM, Koro CE. The effects of antipsychotic therapy on serum lipids: a comprehensive review. Schizophr Res 2004;70:1–17. [5] Casey DE. Dyslipidemia and atypical antipsychoic drugs. J Clin Psychiatry 2004;65:27–35. [6] Henderson DC, Daley TB, Kunkel L, et al. Clozapine and hypertension: a chart review of 82 patients. J Clin Psychiatry 2004; 65:686–9. [7] de Leon J, Susce MT, Johnson M, et al. A clinical study of the association of antipsychotics with hyperlipidemia. Schizophr Res 2007;92:95–102. [8] Meyer JM, Davis VG, Goff DC, McEvoy JP, Nasrallah HA, Davis SM, Rosenheck RA, Daumit GL, Hsiao J, Swartz MS, Stroup TS, Lieberman JA. Change in metabolic syndrome parameters with antipsychotic treatment in the CATIE Schizophrenia Trial: prospective data from phase 1. Schizophr Res 2008;101:273–86. [9] Baptista T, Kin NMKNY. Obesity and related metabolic abnormalities during antipsychotic drug administration: mechanisms, management and research perspectives. Pharmacopsychiatry 2002;35: 205–19. [10] Correll C. Balancing efficacy and safety in treatment with antipsychotics: an expert review of clinical challenges in psychiatry. CNS Spectr. 2007;12:10 (Suppl 17):12–20, 35.
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[11] Utermann G. Apolipoprotein E polymorphisms in health and disease. Am Heart J 1987;113:433–40. [12] Arulmozhi DK, Dwyer DS, Bodhankar SL. Antipsychotic induced metabolic abnormalities: an interaction study with various PPAR modulators in miceLife. Sciences 2006;79(19):1865–72. [13] de Leon J, Correa JC, Ruaño G, et al. Exploring genetic variations that may be associated with the direct effects of some antipsychotics on lipid levels. Schizophr Res 2008;98(1-3):40–6. [14] Meltzer HY, Burnett S, Bastani B, Ramirez LF. Effect of six months of clozapine treatment on the quality of life of chronic schizophrenic patients. Hosp Community Psychiatry 1990;41:892–7. [15] Cohn TA, Sernyak MJ. Metabolic monitoring for patients treated with antipsychotic medications. Can J Psychiatry 2006;51:492–501.
[16] De Hert M, van Eyck D, De Nayer A. Metabolic abnormalities associated with second generation antipsychotics: fact or fiction? Development of guidelines for screening and monitoring. Int Clin Psychopharmacol 2006;21:S11–6. [17] American Diabetes Association, American Psychiatric Association, American Association of Clinical Endocrinologists, North American Association for the Study of Obesity. Consensus development conference on antipsychotic drugs and obesity and diabetes. Diabetes Care 2004;27:596–601. [18] Nasrallah H, McEvoy J, Meyer J, Goff D, Davis S. Low rates of treatment for metabolic disorders in the CATIE schizophrenia trial at baseline: healthcare disparities in schizophrenia. Neuropsychopharmacology 2005;30:S204.